This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Proteases have been recognized as potent drug targets. Our research focuses on the study of intramembrane proteases. In some prokaryotes rhomboids have been shown to play a role in quorum sensing. In humans rhomboids play a key anti-apoptotic role by maintaining mitochondrial integrity. Other isoforms are responsible for cleaving signalling molecules such as epidermal growth factor responsible for cell fate. We have solved the structure of a rhomboid intramembrane protease (also known as peptidase) from Haemophilus influenzae. We now seek to crystallize protease-inhibitor complexes to identify the reaction intermediates for peptide bond catalysis. We also seek to identify the structural features in eukaryotic rhomboids involved in breast cancer and Type 2 diabetes. This will be essential for de novo drug design.